: Human pathological pain is a major unresolved problem. Recent data strongly support the argument that spinal cord glia (astrocytes and microglia) are critically involved in the creation and maintenance of diverse pathological pain states. Spinal cord glia create exaggerated pain states via the release of proinflammatory cytokines (PICs). Recognition of the key importance of spinal cord glia and glial PICs in pathological pain opens new avenues for pain control. There are various treatments available to control glial activation involved in enhanced pain. Interleukin-10 (IL10) is the most promising from a clinical point of view. IL10 is an excellent candidate for preventing and reversing PIC-driven pathological pain states. However, two practical problems need to be overcome. First, control of chronic pain requires chronic delivery of IL10. Second, IL10 cannot cross the blood-brain barrier, thus negating systemic administration. To resolve these issues, we have explored the feasibility of using prolonged spinal release of IL10 induced by gene therapy. Here, adenoviral vectors encoding IL10 are injected into the cerebrospinal fluid surrounding the spinal cord. Our preliminary data provide strong support for the possibility that spinal gene therapy with IL10 will prevent and reverse pathological pain. The aims of the present proposal are three-fold: (1) To determine the breadth of clinically relevant exaggerated pain states that can be prevented and/or reversed by gene therapy-induced IL10 in spinal CSF; (2) To construct a "gutless" adenoviral vector of IL10 which allows virally infected cells to avoid detection and destruction by the immune system; and (3) To characterize the patterns of IL10 release, characterize viral spread and clarity whether peripheral immune functions are impacted by this procedure. Together these studies will test the premise that intrathecal IL10 delivery via gene therapy is worthy of clinical development for controlling diverse pathological pain states. This approach to pain control represents a dramatic departure from all other available therapies.